New organic reactions that employ Lewis bases (nucleophiles) as catalysts have received much less attention than the corresponding areas of Lewis acid catalysis or transition metal catalysis. However, this Lewis base strategy can access innovative and different reactivity patterns unattainable with these established catalysis approaches. The long range goals of these studies are to develop new polarity reversal reactions (Umpolung) catalyzed by Lewis bases and to uncover the fundamental interactions/characteristics that guide them. Our approach focuses on fully developing our recently discovered nucleophile-catalyzed carbonyl anion addition reaction employing acylsilanes and a-keto acids. These processes rely on the insight that acylsilanes and a-keto acids are viable carbonyl anion precursors when exposed to the correct catalytic additions. The use of acylsilanes and a-keto acids as practical acyl anion precursors avoids the potential problem of benzoin formation incurred when using aldehydes as acyl anion precursors. Furthermore, the anions generated from these precursors using achiral and chiral Lewis bases will be added to prochiral electrophiles to produce high value compounds that are immensely important in the construction of health- improving materials such as Pharmaceuticals and compounds to be used as biological probes. Additional related focuses of this proposal include the discovery and development of two related Umpolung reactions: catalytic homoenolate additions and stereoselective vinylogous carbonyl anion additions. These novel, unconventional bond-forming strategies have significant potential to efficiently access target-oriented or diversity-oriented molecules of interest. The proposed research explores the general applicability our organocatalytic carbonyl anion strategies for rapidly synthesizing molecules that directly impact human health. Each of these processes has mechanistic aspects to explore that will provide general information regarding nucleophile-catalyzed processes. In addition, a strong emphasis has been placed on the development of new Lewis base catalysts (achiral and chiral) in order to render many of our current reactions stereoselective. [unreadable] [unreadable] [unreadable]